This invention relates to a method of treating eye disease. Specifically, this invention relates to a method of removing pathological fluid accumulation in subretinal and intra-retinal spaces, by administering P2Y receptor agonists such as certain dinucleotides to a subject in need of such a treatment. The method comprises administering metabolically stable, hydrolysis resistant P2Y receptor agonists, such as certain dinucleotides, in an amount effective to treat the family of blinding conditions comprising retinal detachment and retinal edema.
The retinal pigment epithelium (RPE) lies in the back of the vertebrate eye and forms a barrier that separates the retina from the choroidal blood supply. A critical function of the RPE is to maintain and regulate the hydration of the subretinal space, the extracellular volume that exists between the retina and the RPE. (Marmor, pp. 3-12, in The Retinal Pigment Epithelium, Eds. M. F. Marmor and T. J. Wolfensberger, Oxford University Press, New York, (1998)) This function is achieved by the regulated transport of fluid, ions, and metabolites between the subretinal space and the choroidal blood supply. (Marmor, pp. 420-438, in The Retinal Pigment Epithelium, Eds. M.F. Marmor and T. J. Wolfensberger, Oxford University Press, New York, (1998); Pederson, pp. 1955-1968, in Retina, Ed. S. J. Ryan, Mosby, St. Louis, (1994)). Like all epithelia, the RPE contains two functionally and anatomically distinct membranes: an apical membrane that faces the retina, and a basolateral membrane that faces the choroidal blood supply. In the normal retina, fluid is absorbed across the RPE in the direction of the subretinal space to the choroid. This active absorption of fluid by the RPE, often referred to as the xe2x80x9cRPE pump,xe2x80x9d plays a critical role in maintaining proper attachment of photoreceptors to the apical membrane of the RPE by pumping fluid out of the retinal spaces. (Marmor, pp. 1931-1954, in Retina, Ed. S. J. Ryan, Mosby, St. Louis, (1994); Hughes, et al., pp. xvii, 745, in The Retinal Pigment Epithelium, Eds. M.F. Marmor and T. J. Wolfensberger, Oxford University Press, New York, (1998)).
Retinal detachment is characterized by abnormal accumulation of fluid in the subretinal space leading to detachment of the retina from the underlying retinal pigment epithelium. Retinal edema refers to abnormal accumulation of fluid within the retina itself. Retinal detachment or edema in the central part of the retina (macula) produces significant loss of vision, and can ultimately lead to irreversible blindness. (Yanoff and Duker, Ophthalmology, Mosby, Philadelphia, (1999); Wilkinson, et al., Michels""s Retinal Detachment, 2nd ed. Mosby, St. Louis, (1997)) A wide variety of ocular pathologies can result in retinal detachment or retinal edema. The most common type of retinal detachment is rhegmatogenous retinal detachment, which occurs as a result of single or multiple tears or holes in the retina that permit liquefied vitreous to enter into the subretinal space and create a retinal detachment.
There are no pharmacological approaches employed in the treatment of rhegmatogenous retinal detachment (RRD). The only current treatments for RRD are surgical (scleral buckling, pneumatic retinopexy, or vitrectomy). (Wilkinson, et al., Michels""s Retinal Detachment, 2nd ed., Mosby, St. Louis, (1997)). There are two vital components for successful RRD surgery: reattachment of the retina and repair of the retinal break. The principal difference among the three surgical techniques for treating RRD is in the method employed to facilitate retinal reattachment.
Scleral buckle uses an extraocular buckle (usually a silicone sponge or solid silicone) that is sewn to the sclera towards the detached retina (Wilkinson, et al, Michels""s Retinal Detachment, 2nd ed., Mosby, St. Louis (1997)) The retina usually reattaches over a period of a few days, but may take up to a few weeks. The surgeon may elect to drain the subretinal fluid at the time of operation by inserting a needle through the sclera, choroid, and RPE. In general, the buckle remains permanently sewn to the sclera. In pneumatic retinopexy, a gas bubble is injected directly into the vitreous, and the head is positioned so that the gas bubble acts as a tamponade and covers the retinal break. (Tornambe and Hilton, Ophthalmology 96(6): 772-83 (1989)). The subretinal fluid usually resolves within 1-2 days, but precise head positioning is required to insure that the bubble covers the retinal break. (Tornambe, et al., Am. J. Ophthalmol. 127(6): 741-3 (1999)). Vitrectomy is usually used for complex RRD associated with vitreous traction or hemorrhage, but is occasionally used for simple RRD (Chang, pp. 8.34.1-8.34.6, in Ophthalmology, Eds. M. Yanoff and J. S. Duker, Mosby, Philadelphia, (1999)). The procedure involves making three small incisions through the sclera to allow the introduction of instruments in the vitreous cavity. The vitreous is removed and replaced with a special saline solution. Depending on the type and cause of the detachment, a variety of instruments and techniques are then used to reattach the retina. For simple detachments, the retina is flattened via anterior drainage of the subretinal space by insertion of needle through the retinal tear.
Scleral buckle and vitrectomy often require general anesthesia and can involve hospitalization. Pneumatic retinopexy is usually done in the physician""s office, but requires patient compliance for success. (Hilton and Tornambe, Retina 11(3): 285-94 (1991); Hilton and Brinton, pp. 2093-2112, in Retina, Ed. Stephen J. Ryan, Mosby, Philadelphia, (1999); Han, et al., Am. J. Ophthalmol. 126(5): 658-68 (1998)). Depending on the surgical technique and the surgeon, success rates can vary following single surgery, with lower rates for pneumatic retinopexy and higher rates for scleral buckle. (Tornambe, et al., Am. J. Ophthalmol. 127(6): 741-3 (1999); Han, et al., Am. J. Ophthalmol. 126(5): 658-68 (1998)) The success of retinal detachment surgery is measured in terms of retinal reattachment at any point following surgery (ranging from hours to weeks). Parameters such as visual outcome and patient quality-of-life are not used to assess success of retinal detachment surgery.
The conditions that are commonly associated with the more severe formns of intra-retina edema are diabetic macular edema, exudative age-related macular degeneration (AMD) and clinically significant cystoid macular edema. (Jampol and Po, pp. 999-1008, in Retina, Ed. S. J. Ryan, Mosby, St. Louis, (1994)) Other pathological conditions associated abnormal fluid accumulation in intra-retinal or subretinal spaces include uveitis, central and branch vein occlusion, retinitis pigmentosa, central serous retinopathy, CMV retinitis, and choroidal melanoma. Physical trauma associated with ocular injury following certain surgical procedures (such as cataract surgery) can also produce retinal detachment or edema. (Ahmed and Ai, pp. 8.34.1-8.34.6, in Ophthalmology, , Eds. M. Yanoff and J. Duker, Mosby, Philadelphia, (1999)).
Intra-retina accumulation of fluid in the macula results in decreased visual acuity and is the most common cause of vision loss in patients with diabetic retinopathy, AMD and other ischemic retinopathies such as branch and central retinal vein occlusion. (Jampol and Po, pp. 999-1008, in Retina, Ed. Stephen J. Ryan, Mosby, St. Louis, (1994); Kent, et al., Br. J. Ophthalmol. 84(5): 542-5 (2000)). Macular edema is a frequent complication of uveitis and is commonly seen in patients with retinitis pigmentosa. (Rothova, et al., Br. J. Ophthalmol. 80(4): 332-6 (1996); Fetkenhour, et al., Trans. Am. Acad. Ophthalmol. Otolaryngol. 83(3) Pt 1: OP515-21 (1977)) Macular edema is also a major cause of decreased vision following intraocular surgery (called cystoid macular edema). (Miyake, Surv. Ophthalmol. 28 Suppl: 554-68 (1984)) Accumulation of intra-retina fluid is believed to result from a breakdown of the inner and/or outer blood-retinal barrier. (Kent, et al., Br. J. Ophthalmol. 84(5): 542-5 (2000)) The inner retinal barrier consists of endothelial cells of the retinal vasculature and the outer barrier comprises of the retinal pigment epithelium. Breakdown of the blood-retinal barrier can result in focal leakage of fluid from the vasculature and fluid accumulation within retinal layers or in the subretinal space. The present treatments for retinal edema include systemic and topical administrations of corticosteroid, acetazolamide, and non-steroidal anti-inflammatory drugs, as well as surgical options such as vitrectomy, grid, and focal laser photocoagulation. These therapies show limited utility in patients. The present invention discloses significant improvements in the treatment of retinal edema.
Although modern day RRD surgery has a relatively high success rate (60-90%), it is thought that a pharmaceutical composition that can reattach the retina in cases where surgery failed would be of enormous patient benefit. In addition, if the pharmaceutical composition can reattach the retina in the absence of surgical intervention, it would be most therapeutically useful, particularly in the treatment of rhegmatogenous retinal detachment. The present invention discloses pharmaceutical compositions and methods of use thereof that will significantly improve upon existing treatments for retinal detachment.
A number of pharmacological and surgical approaches are employed to treat cystoid and diabetic macular edema, but they are generally considered empirical and often ineffective. Non-specific anti-inflammatory treatment is used for all types of macular edema, except in cases associated with ischemic retinopathies in which laser treatment is indicated (Kent, et al., Br. J. Ophthalmol. 84 (5): 542-5 (2000)). Corticosteroids are frequently used to treat macular edema, but were shown to be ineffective in a randomized, placebo controlled study (Flach, et al., Am. J. OphthalmoL. 103(4): 479-86 (1987); Flach, et al., Ophthalmology, 97(10): 1253-8 (1990)). Acetazolamide also alleviates certain types of macular edema and is postulated to work via activation of the RPE pump, but systemic tolerance to acetazolamide is poor. (Cox, et al., Arch. Ophthalmol. 106(9):1190-5 (1988)). Focal or grid laser photocoagulation is commonly used to reduce retinal vascular leakage associated with diabetic retinopathy, and is useful in limited cases. ( Ip, et al., In Ophthalmology, London; Philadelphia: Mosby, 8.4.1-8.4.2 (1999); The Diabetic Retinopathy Study Research Group, Ophthalmology 88 (7): 583-600 (1981); Early Treatment Diabetic Retinopathy Study Research Group, Arch. Ophthalmol. 103(12): 1796-806 (1985); The Branch Vein Occlusion Study Group, Am. J. Ophthalmol. 98(3): 271-82 (1984)). In addition, vitrectomy is employed to treat diabetic retinopathies associated with vitreal hemorrhages and/or vitreoretinal traction.(Wilkinson, et al, Michels""s Retinal Detachment, 2nd ed., Mosby, St. Louis, (1997)). There remains a large unmet medical need for a safe, effective treatment of macular edema. (Kent, et al., Br. J. Ophthalmol. 84(5): 542-5 (2000)) The present invention provides significant improvement to patients that suffer from retinal and macular edema.
Previous work has shown that the apical (retinal-facing) membrane of the RPE contains P2Y receptors that can be activated to stimulate fluid transport across the RPE in the direction of the subretinal space to the choroidal blood supply, and this mechanism of action was proposed to facilitate the removal of subretinal fluid in retinal detachment. (Peterson, et al, J. Neurosci. 17(7): 2324-37 (1997)) However, the natural ligands for the P2Y2 receptor are ATP and UTP, both of which are rapidly degraded by ubiquitous extracellular nucleotidases. Therefore, in order for ATP and UTP to be efficacious in the treatment of retinal detachment, these compounds need to be delivered directly into the subretinal space. However, drug delivery into the subretinal space is widely regarded to be unacceptably risky for patients because it involves the insertion of a needle between the retina and RPE, which can result in complications and blindness. Therefore, in order for ATP or UTP to be therapeutically useful, it must be delivered into the intravitreal cavity, which is a much less invasive procedure. However, in order for ATP or UTP to reach the RPE apical membrane, it must diffuse across the retina. The retina is a 200-300 xcexcm thick layer of neuronal, glial, and endothelial tissue, and is one of the most metabolically active tissues in the body when normalized by tissue weight. ATP and UTP are expected to be completely degraded during their diffusion through the retinal layers. The present invention overcomes this limitation by disclosing novel hydrolysis-resistant agonists of the P2Y receptor that are efficacious when delivered into the vitreous, and methods of using such agonists in the treatment of retinal detachment and edema.
Pharmaceutical compositions and methods of use thereof for stimulating removal of extraneous fluid in the retina or subretinal space in a subject in need of such treatment are disclosed. The methods and compositions disclosed in the present invention may be used to stimulate removal of extraneous intra-retinal or subretinal fluid for any reason, including, but not limited to, primary and adjunctive treatments of rhegmatogenous retinal detachment, serous retinal detachment, all forms of cystoid macular edema (uveitis, post-surgical, central and branch vein occlusion, and inherited retinal diseases such as retinitis pigmentosa), and all forms of retinal and macular edema (proliferative and non-proliferative, exudative age-related macular degeneration, and retinopathy of prematurity.)
The present invention discloses methods of treating a subject with retinal detachment or retinal edema by administering pharmaceutical composition according to Formulae I, Ia and Ib via intravitreal injection, intravitreal sustained release or delivery, ocular surface instillation, transcleral injection or infusion, or systemic injection or infusion. The present invention also discloses aqueous, gel, gel-like, and solid formulations for pharmaceutical compositions. A preferred embodiment consisting of a pharmaceutical composition for acute or chronic use in the treatment of retinal detachment and retinal edema is also disclosed.
The method comprises administration to a subject an effective dose of a pharmaceutical composition comprising a P2Y receptor ligand with or without therapeutic and adjuvant agents commonly used to treat or manage retinal detachment. An effective dose of the composition is that amount which activates P2Y receptors and facilitates outflow of fluid, sufficient to effectuate removal of extraneous fluid from the retina or subretinal space. Although P2Y2 receptor agonists are optimally effective in facilitating the removal of extraneous retinal or subretinal fluids, agonists of other P2Y receptor subtypes, specifically P2Y1, P2Y4, P2Y6, and P2Y11, are also effective.
The pharmaceutical compositions useful in this invention comprise P2Y2 receptor agonists, including certain adenine-, uridine-, and cytidine-containing dinucleotides. Such pharmaceutical compounds include dinucleotide analogues, which are selective agonists of the P2Y receptor on epithelial cells of the retinal pigment epithelium. Activation of P2Y receptors by such agonists is associated with elevated intracellular calcium levels and increased fluid transport across the RPE.